Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1.
Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1.
复制标题
1型神经纤维瘤病的自发和工程化大动物模型。
DOI：
10.3390/ijms22041954
复制
发表时间：
2021-02-16
影响因子：
5.6
通讯作者：
Largaespada DA
中科院分区：
文献类型：
--
作者：
Osum SH;Watson AL;Largaespada DA
动物模型对于理解人类疾病生物学和开发新疗法至关重要。到目前为止，用于研究人类疾病流行问题的最常见动物是老鼠。小鼠模型是强大的研究工具，因为它们的小尺寸，有限的寿命和明确的遗传背景使研究人员能够轻松操纵它们的基因组并在一般实验室空间中维持大量动物。然而，正是这些属性使它们与人类如此不同，并部分解释了为什么这些模型不能准确预测人类患者的药物反应。神经纤维瘤病（NF）尤其如此，神经纤维瘤病是一组使个体易患神经系统肿瘤的遗传疾病，其中最常见的是1型神经纤维瘤病（NF 1）。尽管多年的研究，仍然有许多未回答的问题和几个有效的治疗NF 1。基因工程小鼠极大地提高了我们对NF 1许多方面的理解，但它们并不能解释疾病的整体复杂性，而且由于体型和生理学的差异，一些发现并不能很好地转化为人类。此外，NF 1小鼠模型严重依赖于Cre-Lox系统，这不能准确地反映伴随人类肿瘤发展的杂合性自发丢失的分子机制。自发的和基因工程的大型动物模型可能会提供一个有价值的补充，啮齿类动物的研究NF 1。自然发生的疾病比较模型是一个有吸引力的前景，因为它们发生在异质性遗传背景上，并且是由于自发而不是工程突变。使用自然发生疾病的动物对研究骨肉瘤、淋巴瘤和糖尿病是有效的。自发性NF样症状，包括神经纤维瘤和恶性外周神经鞘瘤（MPNST）已被记录在几个大型动物物种，并与人类NF 1共享生物学和临床相似性。这些动物可以为NF 1的复杂生物学提供额外的见解，并可能为临床前试验提供平台。此外，最近已经开发了NF 1的基因工程猪模型，并显示出与NF 1患者相似的各种临床特征。它们的大尺寸和相对较长的寿命允许纵向成像研究和使用人类设备评估创新的手术技术。与人类更大的遗传、解剖学和生理学相似性使得能够工程化在人类患者中发现的精确疾病等位基因，并且使它们在患者临床试验之前理想地用于小分子、细胞和基因疗法的临床前药代动力学和药效学研究。人类和自然发生疾病的动物之间的比较基因组研究，以及大型动物疾病模型的临床前研究，可能有助于确定治疗干预的新靶点，并加快新疗法的转化。在这篇综述中，我们讨论了新的基因工程大型动物模型的NF 1和自发的NF样表现在大型动物的情况下，特别强调这些比较模型可以作为一个重要的翻译中介专门的小鼠模型和NF 1患者。
Animal models are crucial to understanding human disease biology and developing new therapies. By far the most common animal used to investigate prevailing questions about human disease is the mouse. Mouse models are powerful tools for research as their small size, limited lifespan, and defined genetic background allow researchers to easily manipulate their genome and maintain large numbers of animals in general laboratory spaces. However, it is precisely these attributes that make them so different from humans and explains, in part, why these models do not accurately predict drug responses in human patients. This is particularly true of the neurofibromatoses (NFs), a group of genetic diseases that predispose individuals to tumors of the nervous system, the most common of which is Neurofibromatosis type 1 (NF1). Despite years of research, there are still many unanswered questions and few effective treatments for NF1. Genetically engineered mice have drastically improved our understanding of many aspects of NF1, but they do not exemplify the overall complexity of the disease and some findings do not translate well to humans due to differences in body size and physiology. Moreover, NF1 mouse models are heavily reliant on the Cre-Lox system, which does not accurately reflect the molecular mechanism of spontaneous loss of heterozygosity that accompanies human tumor development. Spontaneous and genetically engineered large animal models may provide a valuable supplement to rodent studies for NF1. Naturally occurring comparative models of disease are an attractive prospect because they occur on heterogeneous genetic backgrounds and are due to spontaneous rather than engineered mutations. The use of animals with naturally occurring disease has been effective for studying osteosarcoma, lymphoma, and diabetes. Spontaneous NF-like symptoms including neurofibromas and malignant peripheral nerve sheath tumors (MPNST) have been documented in several large animal species and share biological and clinical similarities with human NF1. These animals could provide additional insight into the complex biology of NF1 and potentially provide a platform for pre-clinical trials. Additionally, genetically engineered porcine models of NF1 have recently been developed and display a variety of clinical features similar to those seen in NF1 patients. Their large size and relatively long lifespan allow for longitudinal imaging studies and evaluation of innovative surgical techniques using human equipment. Greater genetic, anatomic, and physiologic similarities to humans enable the engineering of precise disease alleles found in human patients and make them ideal for preclinical pharmacokinetic and pharmacodynamic studies of small molecule, cellular, and gene therapies prior to clinical trials in patients. Comparative genomic studies between humans and animals with naturally occurring disease, as well as preclinical studies in large animal disease models, may help identify new targets for therapeutic intervention and expedite the translation of new therapies. In this review, we discuss new genetically engineered large animal models of NF1 and cases of spontaneous NF-like manifestations in large animals, with a special emphasis on how these comparative models could act as a crucial translational intermediary between specialized murine models and NF1 patients.
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影响因子：
3.8
作者：
Brossier NM;Carroll SL
通讯作者：
Carroll SL
影响因子：
64.8
作者：
De Raedt, Thomas;Beert, Eline;Cichowski, Karen
通讯作者：
Cichowski, Karen
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作者：
Beert, Eline;Brems, Hilde;Legius, Eric
通讯作者：
Legius, Eric
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3.2
作者：
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通讯作者：
Bourdeaut, Franck
影响因子：
4.4
作者：
Dammann, Insa;Wemheuer, Wiebke M.;Schulz-Schaeffer, Walter
通讯作者：
Schulz-Schaeffer, Walter